Nonalcoholic Fatty Liver Disease Progresses into Severe NASH when Physiological Mechanisms of Tissue Homeostasis Collapse
* University of Buenos Aires, Institute of Medical Research A Lanari, Buenos Aires, Argentina
** National Scientific and Technical Research Council (CONICET) - University of Buenos Aires, Institute of Medical Research (IDIM), Department of Clinical and Molecular Hepatology, Buenos Aires, Argentina
*** National Scientific and Technical Research Council (CONICET)-University of Buenos Aires, Institute of Medical Research (IDIM), Department of Molecular Genetics and Biology of Complex Diseases, Buenos Aires, Argentina
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"documento" => "article" "crossmark" => 0 "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/" "subdocumento" => "edi" "cita" => "Ann Hepatol. 2018;17:180-1" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 100 "formatos" => array:3 [ "EPUB" => 18 "HTML" => 46 "PDF" => 36 ] ] "en" => array:8 [ "idiomaDefecto" => true "titulo" => "Natural Extracts as Modifiers of Intracellular Lipid Handling" "tienePdf" => "en" "tieneTextoCompleto" => "en" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "180" "paginaFinal" => "181" ] ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Rosellina Margherita Mancina, Piero Pingitore" "autores" => array:2 [ 0 => array:2 [ "nombre" => "Rosellina Margherita" "apellidos" => "Mancina" ] 1 => array:2 [ "nombre" => "Piero" "apellidos" => "Pingitore" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1665268119301486?idApp=UINPBA00004N" "url" => "/16652681/0000001700000002/v1_201905140709/S1665268119301486/v1_201905140709/en/main.assets" ] "en" => array:16 [ "idiomaDefecto" => true "titulo" => "Nonalcoholic Fatty Liver Disease Progresses into Severe NASH when Physiological Mechanisms of Tissue Homeostasis Collapse" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "182" "paginaFinal" => "186" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Silvia Sookoian, Carlos J. Pirola" "autores" => array:2 [ 0 => array:4 [ "nombre" => "Silvia" "apellidos" => "Sookoian" "email" => array:1 [ 0 => "sookoian.silvia@lanari.fmed.uba.ar" ] "referencia" => array:3 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">**</span>" "identificador" => "aff0010" ] 2 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "Carlos J." "apellidos" => "Pirola" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">***</span>" "identificador" => "aff0015" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "University of Buenos Aires, Institute of Medical Research A Lanari, Buenos Aires, Argentina" "etiqueta" => "*" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "National Scientific and Technical Research Council (CONICET) - University of Buenos Aires, Institute of Medical Research (IDIM), Department of Clinical and Molecular Hepatology, Buenos Aires, Argentina" "etiqueta" => "**" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "National Scientific and Technical Research Council (CONICET)-University of Buenos Aires, Institute of Medical Research (IDIM), Department of Molecular Genetics and Biology of Complex Diseases, Buenos Aires, Argentina" "etiqueta" => "***" "identificador" => "aff0015" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "*" "correspondencia" => "Corresponding author." ] ] ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "f0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 462 "Ancho" => 656 "Tamanyo" => 32200 ] ] "descripcion" => array:1 [ "en" => "<p id="sp0005" class="elsevierStyleSimplePara elsevierViewall">Phenotypic modulation of NAFLD-severity by molecules derived from white (adipokines) and brown (batokines) adipose tissue by inducing or protecting against the progression of the disease. Adipose tissue-derived factors can promote the progression of NAFLD towards severe histological stages (NASH-fibrosis and NASHcirrhosis). This effect can be modulated by the release of adipokines that directly trigger an inflammatory response in the liver tissue or indirectly modulate related phenotypes, such as insulin resistance (up-arrows). Metabolically dysfunctional adipose tissue, which is often infiltrated by macrophages and crown-like histological structures, may also show impaired production of anti-inflammatory adipokines, which may favor NAFLD progression into aggressive phenotypes by preventing its protective effects on the liver tissue (down-arrows). SFRP5: secreted frizzled-related protein 5. UCP1: uncoupling protein 1. FGF21: fibroblast growth factor 21. TNF a: tumor necrosis factor a. IL1 and IL6: interleukin 1 and 6. MCP-1: mono-cyte chemotactic protien-1.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="p0005" class="elsevierStylePara elsevierViewall">Opinion Article on the MS published in the <span class="elsevierStyleItalic">Journal of Clinical Investigation</span> entitled: <span class="elsevierStyleBold"><span class="elsevierStyleItalic">Hepatic neuregulin 4 signaling defines an endocrine checkpoint for steatosis-to-NASH progression.</span></span></p><p id="p0010" class="elsevierStylePara elsevierViewall">Nonalcoholic fatty liver disease (NAFLD) is regarded as the most prevalent chronic liver disease worldwide.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Although the disease is considered benign and having a relatively good prognosis when the diagnosis is made at earlier histological stages, the progression into severe clinical forms, including nonalcoholic steatohepatitis (NASH), NASH-fibrosis and NASH-cirrhosis, imposes tremendous medical challenges.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> For these reasons, extensive body of research aimed at the search for factors and or causes that modify the natural history of NAFLD is currently being conducted.</p><p id="p0015" class="elsevierStylePara elsevierViewall">The complexity of the NAFLD-associated clinical picture, specifically the association with co-morbidities such as type 2 diabetes (T2D),<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> obesity and cardiovascular disease,<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2</span></a><span class="elsevierStyleSup">–</span><a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> suggests the presence of an even more intricate network of pathogenic mechanisms that not only interact with each other but also increase the chances of having a more dramatic and severe phenotype. In this regard, the cross-talk between NAFLD and adipose tissue has gained particular attention of researchers and practitioners because cytokines derived from either white fat-WAT (adi-pokines) or brown fat-BAT (batokines) play a remarkable role in the development and maintenance of NAFLD disease severity. <a class="elsevierStyleCrossRef" href="#f0005">Figure 1</a> illustrates the concept of phenotypic modulation of NAFLD severity by molecules derived from adipose tissue that act as paracrine and endocrine hormones.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a>,<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a></p><elsevierMultimedia ident="f0005"></elsevierMultimedia><p id="p0020" class="elsevierStylePara elsevierViewall">Pathways involved in organ damage and injury, including cellular apoptosis or other process associated with cell death, as well as persistent tissue inflammation and the consequent fibrogenesis, are all triggered by multiple factors, including genetic predisposition and epigenetic modifiers.<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">7</span></a><span class="elsevierStyleSup">–</span><a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> Nevertheless, the exact mechanism/s that promote the transition of NAFL (nonalcoholic fatty liver) to NASH remain(s) elusive.</p><p id="p0025" class="elsevierStylePara elsevierViewall">Guo, <span class="elsevierStyleItalic">et al.</span> recently reported the role of Neuregulin 4 <span class="elsevierStyleItalic">(Nrg4)</span>, an adipose tissue-enriched endocrine factor, in the development of NASH.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> Specifically, the authors used a mouse model of high-fat-fructose diet-induced NASH that recapitulates main histological features of human NASH.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> Key molecular findings associated with the presence of NASH in mice were:<ul class="elsevierStyleList" id="l0005"><li class="elsevierStyleListItem" id="u0005"><span class="elsevierStyleLabel">•</span><p id="p0030" class="elsevierStylePara elsevierViewall">Cell death, which was associated with both increased phosphorylation of the member of the MAP-kinase family JNK1/2 and reduced protein levels of the inhibitor of apoptotic and necroptotic cell death c-FLIPL (Caspase 8 and FADD-Like Apoptosis Regulatory Protein, CFLAR), and</p></li><li class="elsevierStyleListItem" id="u0010"><span class="elsevierStyleLabel">•</span><p id="p0035" class="elsevierStylePara elsevierViewall">Significantly decreased mRNA expression of <span class="elsevierStyleItalic">Nrg4</span> in epididymal WAT and BAT.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a></p></li></ul></p><p id="p0040" class="elsevierStylePara elsevierViewall">Subsequent <span class="elsevierStyleItalic">Nrg4</span> gain- and loss-of-function studies in mouse models showed that restoration of <span class="elsevierStyleItalic">Nrg4</span> signaling protects animals from NASH; specifically, <span class="elsevierStyleItalic">Nrg4</span> signaling protects animals from stress-induced cell death through interaction with c-FLIP.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> Notably, genes associated with fibrogenesis <span class="elsevierStyleItalic">(Col1a1, Acta2, Tgfb1</span>, and <span class="elsevierStyleItalic">Mmp13)</span> and inflammation <span class="elsevierStyleItalic">(Tnfa, Il1b, Il12b, Nos2, Ccl2, Ccl5</span>, and <span class="elsevierStyleItalic">Adgre1)</span> were upregulated in mice lacking <span class="elsevierStyleItalic">Nrg4</span>, suggesting that <span class="elsevierStyleItalic">Nrg4</span> deficiency exacerbated liver inflammation and fibrosis following NASH-diet feeding.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> It is worth noting that a similar profile in human NAFLD was described by our research group.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a></p><p id="p0045" class="elsevierStylePara elsevierViewall">Considering the aforementioned findings collectively, it is plausible to hypothesize that NAFLD progression is a process in which physiological mechanisms of tissue homeostasis collapse. There is compelling evidence from human studies supporting this hypothesis. For instance, ballooning degeneration —a hallmark histological feature of NAFLD severity and NASH progression— is associated with down-regulation of liver HSP27 gene and protein expression.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> HSP27 is a member of the heat shock family of proteins also known as stress-responsive protein 27. Furthermore, NASH development is associated with mitochondrial dysfunction, increased mitochondrial DNA (mtDNA) genetic diversity, down-regulation of liver expression of genes of the oxidative phosphorylation (OXPHOS) chain, and aberrant patterns of mtDNA methylation.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a>,<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a>,<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a>,<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a></p><p id="p0050" class="elsevierStylePara elsevierViewall">The first question that immediately emerges is what factor/s trigger this complex picture?</p><p id="p0055" class="elsevierStylePara elsevierViewall">Robust evidence supports the notion that NAFLD severity is associated with metabolic stress. In fact, it has been linked with increased transamination reactions that would promote coping with the liver metabolic derangement.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> This, in turn, leads to changes in the amounts of amino acids released into the circulation, particularly in pathways related to glutamic acid. <a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a>,<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> As reported recently, glutaminolysis controls accumulation of myofibroblast hepatic stellate cells.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> Deregulated liver metabolism also leads to aberrant patters of hedgehog signaling<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a>,<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> and insufficient ketogenesis, which result in extensive hepatocyte injury and inflammation, decreased glycemia, and deranged hepatic TCA (tricarboxylic acid) cycle intermediate concentrations.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a>,<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a></p><p id="p0060" class="elsevierStylePara elsevierViewall">The second, and even more difficult to answer question is why a brown fat-derived secreted factor is important in maintaining liver tissue homeostasis?</p><p id="p0065" class="elsevierStylePara elsevierViewall">It is well known that systemic metabolic homeostasis is regulated by the “in concert” action of a myriad of tissue-derived factors, which originate from different sources, including adipose tissue, gut, muscle, liver and bone. These hormones / growth factors / bioactive molecules basically sense global metabolism and energy homeostasis. These mechanisms may eventually fail to ensure cell / tissue physiological functions. Alternatively, they can simply malfunction because the affected cell / tissue has abnormally increased its metabolic demands, which might occur in common diseases like NAFLD and obesity, as well as in cancer. In the latter case, epidermal growth factors (EGFs) are critically implicated in cancer growth and survival by engaging a number of proteins via the ErbB (Tyrosine Kinase-Type Cell Surface Receptor HER2) family of proteins. In this regard, the neuregulins, including NRG4, activate type-1 growth factor receptors involved in initiating cell-to-cell signaling through tyrosine phosphorylation.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> Neuregulins transduce signals via activation of the ErbB receptors, specifically ErbB4.</p><p id="p0070" class="elsevierStylePara elsevierViewall">Evidence supporting the role of <span class="elsevierStyleItalic">Nrg4</span> in NAFLD and metabolic syndrome, while presently limited, is promising. For example, it has been shown that <span class="elsevierStyleItalic">Nrg4</span> attenuates hepatic lipogenic signaling and preserves glucose and lipid homeostasis in experimental models of obesity.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> In this particular study, Wang, <span class="elsevierStyleItalic">et al.</span> demonstrated in mice that <span class="elsevierStyleItalic">Nrg4</span> negatively regulates <span class="elsevierStyleItalic">de novo</span> lipogenesis mediated by Lxr (liver X receptor) and Srebplc (sterol regulatory element binding transcription factor 1) in a cell-autonomous manner.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a></p><p id="p0075" class="elsevierStylePara elsevierViewall">Data yielded by human studies is not only insufficient, but is also inconclusive. Kang, <span class="elsevierStyleItalic">et al.</span> found that the circulating NRG4 levels are increased in patients with type 2 diabetes and positively correlate with serum glucose level, HOMA-IR, and serum triglycerides;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> however, opposite results were reported by Yan, <span class="elsevierStyleItalic">et al</span>.<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> Controversial evidence has also been derived from studies of gestational diabetes.<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a>,<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> For example, Cai, <span class="elsevierStyleItalic">et al.</span> reported that NRG4 might protect against metabolic syndrome development.<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> Similarly, Dai, <span class="elsevierStyleItalic">et al.</span> found that patients with NAFLD also show reduced levels of serum NRG4.<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a></p><p id="p0080" class="elsevierStylePara elsevierViewall">The question that still remains to be answered is whether the role of <span class="elsevierStyleItalic">Nrg4</span> in protecting hepatocytes from apoptosis and necroptosis triggered by metabolic stress is mediated by a circulating endocrine signaling released from WAT or BAT, or if it is a truly liver-specific derived <span class="elsevierStyleItalic">Nrg4.</span> NRG4 human liver gene and protein expression levels are considerably low (<a href="http://www.proteinatlas.org/">http://www.proteinatlas.org/</a> ENSG00000169752-NRG4/tissue). Moreover, it is presently unclear whether <span class="elsevierStyleItalic">Nrg4</span> signaling is mediated by interaction with hepatocytes or whether the actual effector/s of <span class="elsevierStyleItalic">Nrg4</span> are non-liver related resident cells found in NAFLD and NASH. Hence, what exactly determines that <span class="elsevierStyleItalic">Nrg4</span> is a key molecule in protecting the liver from severe NAFLD is uncertain. There are many possibilities, including the fact that <span class="elsevierStyleItalic">Nrg4</span> indeed controls insulin sensitivity and secretion, as <span class="elsevierStyleItalic">Nrg4</span> seems to be a potent insulin releaser.<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> or macrophages migration into the liver. Still, Guo, <span class="elsevierStyleItalic">et al.</span> took the first steps toward unraveling the mechanisms involving the role of <span class="elsevierStyleItalic">Nrg4</span> in protecting fatty liver from severe NASH. A list of Gene Ontology (GO) terms and biological process for NRG4 gene and its interaction network are shown in <a class="elsevierStyleCrossRef" href="#t0005">table 1</a> and <a class="elsevierStyleCrossRef" href="#f0010">figure 2</a>, respectively. It is clear that this molecule seems to play a key role in ensuring effective protection against the progression of NAFLD by opposing caspase-mediated cell death. Interestingly, human “knock-out” for NRG4 has been identified; however, its phenotypic manifestation in the liver remains to be characterized.<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a></p><elsevierMultimedia ident="t0005"></elsevierMultimedia><elsevierMultimedia ident="f0010"></elsevierMultimedia><p id="p0085" class="elsevierStylePara elsevierViewall">In conclusion, there is substantial evidence suggesting that dysregulation of molecular mediators of metabolic homeostasis modulates the natural history of NAFLD. Both their upregulation and deficiency can either cause or exacerbate an adverse phenotype by evading from protective mechanisms against liver damage (<a class="elsevierStyleCrossRef" href="#f0005">Figure 1</a>). Hence, the evolution of NAFLD into severe NASH is mediated by loss of systemic and/ or local protective mechanisms of organ damage.</p></span>" "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2018-01-23" "fechaAceptado" => "2018-01-23" "PalabrasClave" => array:1 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1109517" "palabras" => array:4 [ 0 => "NAFLD" 1 => "NASH" 2 => "Fibrosis" 3 => "Metabolic stress" ] ] ] ] "tieneResumen" => true "resumen" => array:1 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span id="abs0010" class="elsevierStyleSection elsevierViewall"><p id="sp0020" class="elsevierStyleSimplePara elsevierViewall">Phenotypic modulation of NAFLD-severity by molecules derived from white (adipokines) and brown (batokines) adipose tissue may be important in inducing or protecting against the progression of the disease. Adipose tissue-derived factors can promote the progression of NAFLD towards severe histological stages (NASH-fibrosis and NASHcirrhosis).</p><p id="sp0025" class="elsevierStyleSimplePara elsevierViewall">This effect can be modulated by the release of adipokines or batokines that directly trigger an inflammatory response in the liver tissue or indirectly modulate related phenotypes, such as insulin resistance. Metabolically dysfunctional adipose tissue, which is often infiltrated by macrophages and crown-like histological structures, may also show impaired production of anti-inflammatory cytokines, which may favor NAFLD progression into aggressive phenotypes by preventing its protective effects on the liver tissue.</p></span>" ] ] "multimedia" => array:3 [ 0 => array:7 [ "identificador" => "f0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 462 "Ancho" => 656 "Tamanyo" => 32200 ] ] "descripcion" => array:1 [ "en" => "<p id="sp0005" class="elsevierStyleSimplePara elsevierViewall">Phenotypic modulation of NAFLD-severity by molecules derived from white (adipokines) and brown (batokines) adipose tissue by inducing or protecting against the progression of the disease. Adipose tissue-derived factors can promote the progression of NAFLD towards severe histological stages (NASH-fibrosis and NASHcirrhosis). This effect can be modulated by the release of adipokines that directly trigger an inflammatory response in the liver tissue or indirectly modulate related phenotypes, such as insulin resistance (up-arrows). Metabolically dysfunctional adipose tissue, which is often infiltrated by macrophages and crown-like histological structures, may also show impaired production of anti-inflammatory adipokines, which may favor NAFLD progression into aggressive phenotypes by preventing its protective effects on the liver tissue (down-arrows). SFRP5: secreted frizzled-related protein 5. UCP1: uncoupling protein 1. FGF21: fibroblast growth factor 21. TNF a: tumor necrosis factor a. IL1 and IL6: interleukin 1 and 6. MCP-1: mono-cyte chemotactic protien-1.</p>" ] ] 1 => array:7 [ "identificador" => "f0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 599 "Ancho" => 664 "Tamanyo" => 43263 ] ] "descripcion" => array:1 [ "en" => "<p id="sp0010" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">NRG4 interaction network. Gene-gene functional network construction was done using GeneMANIA, available at:</span><span class="elsevierStyleInterRef" id="int2030" href="https://github.com/GeneMANIA/">https://github.com/GeneMANIA/</span> genemania; visualization was performed by Cytoscape (<span class="elsevierStyleInterRef" id="int0030" href="http://apps.cytoscape.org/apps/GeneMania">http://apps.cytoscape.org/apps/GeneMania</span>). NRG4: <span class="elsevierStyleItalic">neuregulin 4; CFLAR CASP8 and FADD like apoptosis regulator; MAPK8: mitogen-activated protein kinase 8. CASP3: caspase 3. AKT1: AKT serine/threonine kinase 1. APPL1: adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 1. TNFSF10: tumor necrosis factor superfamily member 10. CASP10: caspase 10. PHLPP1: PH domain and leucine rich repeat protein phosphatase 1. DIABLO: diablo IAP-binding mitochondrial protein. CASP8: caspase 8. FADD: Fas associated via death domain. EGFR: epidermal growth factor receptor. STK3: serine/threonine kinase 3. MAP2K7: mitogen-activated protein kinase kinase 7. RICTOR: RPTOR independent companion of MTOR complex 2. PAK1: p21 (RAC1) activated kinase 1. BAD: BCL2 associated agonist of cell death. THEM4: thioesterase superfamily member 4. MTOR: mechanistic target of rapamycin. DFFA: DNA fragmentation factor subunit alpha. DYNLL2: dynein light chain LC8-type 2. GAS2: growth arrest specific 2. JUN: Jun proto-oncogene. AP-1 transcription factor subunit. REL REL proto-oncogene. NF-</span> κ<span class="elsevierStyleItalic">B</span><span class="elsevierStyleItalic">subunit.</span></p>" ] ] 2 => array:7 [ "identificador" => "t0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "<p id="np0005" class="elsevierStyleSimplePara elsevierViewall">NRG4 (Neuregulin 4) is a protein coding gene. Among its related pathways are RET signaling (REarranged during Transfection) and signaling by ERBB2. RET (Ret Proto-Oncogene) encodes one of the receptor tyrosine kinases, which are cell-surface molecules that transduce signals for cell growth and differentiation. ERBB2 (Erb-B2 Receptor Tyrosine Kinase 2) encodes a member of the epidermal growth factor (EGF) receptor family of receptor tyrosine kinases; this protein has no ligand binding domain of its own and therefore cannot bind growth factors. GO annotations related to NRG4 include receptor binding and growth factor activity.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">GO ID \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">GO term. \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">GO:0000165 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MAPK cascade. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">GO:0014066 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Regulation of phosphatidylinositol 3-kinase signaling. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">GO:0018108 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Peptidyl-tyrosine phosphorylation. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">GO:0035556 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Intracellular signal transduction. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">GO:0038111 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Interleukin-7-mediated signaling pathway. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">GO:0038128 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ERBB2 signaling pathway. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">GO:0043547 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Positive regulation of GTPase activity. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">GO:0046854 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Phosphatidylinositol phosphorylation. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">GO:0048015 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Phosphatidylinositol-mediated signaling. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">GO:0048513 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Animal organ development. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">GO:1901185 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Negative regulation of ERBB signaling pathway. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">GO:2000145 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Regulation of cell motility. \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2030503.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="sp0015" class="elsevierStyleSimplePara elsevierViewall">Gene Ontology (GO) - Biological Process for NRG4 Gene.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bs0010" "bibliografiaReferencia" => array:28 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1." 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 1 | 0 | 1 |
| 2024 October | 10 | 17 | 27 |
| 2024 September | 12 | 14 | 26 |
| 2024 August | 17 | 17 | 34 |
| 2024 July | 19 | 14 | 33 |
| 2024 June | 41 | 10 | 51 |
| 2024 May | 35 | 15 | 50 |
| 2024 April | 37 | 13 | 50 |
| 2024 March | 36 | 11 | 47 |
| 2024 February | 36 | 8 | 44 |
| 2024 January | 32 | 5 | 37 |
| 2023 December | 33 | 13 | 46 |
| 2023 November | 27 | 9 | 36 |
| 2023 October | 26 | 15 | 41 |
| 2023 September | 19 | 6 | 25 |
| 2023 August | 26 | 12 | 38 |
| 2023 July | 25 | 5 | 30 |
| 2023 June | 24 | 2 | 26 |
| 2023 May | 63 | 4 | 67 |
| 2023 April | 49 | 1 | 50 |
| 2023 March | 50 | 8 | 58 |
| 2023 February | 35 | 3 | 38 |
| 2023 January | 20 | 2 | 22 |
| 2022 December | 25 | 7 | 32 |
| 2022 November | 23 | 10 | 33 |
| 2022 October | 17 | 3 | 20 |
| 2022 September | 30 | 14 | 44 |
| 2022 August | 24 | 5 | 29 |
| 2022 July | 23 | 12 | 35 |
| 2022 June | 16 | 6 | 22 |
| 2022 May | 9 | 9 | 18 |
| 2022 April | 19 | 9 | 28 |
| 2022 March | 22 | 10 | 32 |
| 2022 February | 33 | 5 | 38 |
| 2022 January | 54 | 5 | 59 |
| 2021 December | 43 | 9 | 52 |
| 2021 November | 24 | 14 | 38 |
| 2021 October | 21 | 9 | 30 |
| 2021 September | 20 | 12 | 32 |
| 2021 August | 24 | 6 | 30 |
| 2021 July | 18 | 6 | 24 |
| 2021 June | 10 | 10 | 20 |
| 2021 May | 22 | 10 | 32 |
| 2021 April | 51 | 16 | 67 |
| 2021 March | 53 | 5 | 58 |
| 2021 February | 21 | 13 | 34 |
| 2021 January | 27 | 8 | 35 |
| 2020 December | 23 | 8 | 31 |
| 2020 November | 34 | 10 | 44 |
| 2020 October | 25 | 4 | 29 |
| 2020 September | 26 | 6 | 32 |
| 2020 August | 31 | 10 | 41 |
| 2020 July | 30 | 17 | 47 |
| 2020 June | 26 | 2 | 28 |
| 2020 May | 15 | 7 | 22 |
| 2020 April | 18 | 1 | 19 |
| 2020 March | 16 | 8 | 24 |
| 2020 February | 12 | 10 | 22 |
| 2020 January | 11 | 4 | 15 |
| 2019 December | 17 | 8 | 25 |
| 2019 November | 10 | 7 | 17 |
| 2019 October | 17 | 7 | 24 |
| 2019 September | 22 | 5 | 27 |
| 2019 August | 17 | 5 | 22 |
| 2019 July | 18 | 4 | 22 |
| 2019 June | 9 | 7 | 16 |
| 2019 May | 10 | 18 | 28 |
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